Mycoplasma pneumoniae is the cause of community acquired pneumonia in 20-30% of cases, and also causes tracheobronchitis, pharyngitis and bronchiolitis. We have recently shown that M. pneumoniae is present in the airways of patients with chronic, stable asthma, and that treatment with a macrolide improves lung function, but only in those asthmatics who demonstrate positivity for M. pneumoniae by polymerase chain reaction (PCR). Chronic M. pulmonis infection in the rat results in increased expression of the neurokinin-1 (NK-1) receptor, the ligand for substance P, increased substance P sensitivity and vascular remodeling. Additionally, substance P increases fibroblast proliferation. Preliminary data from our laboratory demonstrates that M. pneumoniae added to epithelial cell culture induces substance P production, a new observation. Therefore, we hypothesize that infection with M. pneumoniae modifies airway responses in asthmatics by increasing substance P sensitivity and airway fibroblast proliferation, resulting in altered airway structure (remodeling) and function. Therapy with a neurokinin receptor antagonist will reduce airway edema, airway inflammation and fibroblast proliferation, particularly in those patients where M. pneumoniae is present in the airway. To test this hypothesis, we will first determine expression of the tachykinins substance P and neurokinin A, their receptors, airway vascularity and collagen deposition in the airway mucosa of normal controls and asthmatic subjects who are PCR(+) and (-) for M. pneumoniae. Using an in vitro model of M. pneumoniae infection, we will determine the role of substance P on the bronchial epithelial cell inflammatory response and airway fibroblast proliferative response after exposure to M. pneumoniae in normal controls and PCR (+) and PCR (-) asthmatic subjects. We then will determine if substance P sensitivity is increased in PCR (+) asthmatics by performing substance P inhalational challenges, and assessing airway function and edema. Finally, we will determine changes in airway function, inflammation and edema after treatment with a neurokinin antagonist. Information learned from this proposal will allow us to determine whether the presence of M. pneumoniae in the airway alters airway function and contributes to remodeling by increasing airway vascularity and collagen deposition. The presence of M. pneumoniae in the lower airway may result in a unique asthma phenotype that may require treatment focusing upon neurogenic inflammation.